MARBLES stands for Markers of Autism Risk in Babies—Learning Early Signs. The study investigates “biological and environmental triggers that children are exposed to prenatally and post-partum”: Some 100 women who have a biological autistic child and who are pregnant, or who are planning on becoming pregnant, are participating in MARBLES, which began in 2006. Researchers from the UC Davis-M.I.N.D. Institute are collecting blood, urine, hair, saliva, and breast milk (if the mother is breast feeding), as well as dust from participants’ houses, and mothers are interviewed and medical records examined. It’s noted that MARBLES is “unique” because

follows mothers before, during, and after their pregnancies, allowing us to obtain information about the pre-natal and post-natal environment to which the baby is exposed.? By gathering information in real-time we increase the accuracy of the information collected and will be able to better understand and observe the biological and behavioral changes that may occur in the mother and/or baby throughout the pregnancy and early childhood period.

The November 22nd InsideBayArea opens by suggesting that people’s homes “might reveal clues for solving one of the biggest mysteries of modern medicine: the cause of a rapid rise in autistic children.” Besides collecting dust with a “special vaccuum,” researchers are also noting what household cleaners soaps, beauty products, electronics, and types of paint, each family uses. And, when Danielle Bell of Danville—whose almost 4-year-old son Jake is autistic—had her now 8-month-old daughter, Layla, researchers were present and “took for laboratory analysis the umbilical cord, a portion of the placenta and what is known as meconium, or the baby’s first bowel movement.”

In the search for a cause, for some of us, it could be said that our homes indeed contain “clues” about autism, in our very selves, in our genes, and not so much is to be revealed by analyzin the dust or the types household cleaning products.

Aside from discovering our housekeeping habits……..

“[A] sweeping theory of brain development that would change the way mental disorders like autism and schizophrenia are understood”——a “new idea” that “provides psychiatry with perhaps its grandest working theory since Freud, and one that is grounded in work at the forefront of science”: Today’s New York Times uses such grand language to introduce a new theory of psychiatric disorders in which parents’ genes are “in competition.” The theory is the work of Bernard Crespi, a biologist at Simon Fraser University in Canada, and Christopher Badcock, a sociologist at the London School of Economics. Here’s how the New York Times describes it:

Dr. Crespi and Dr. Badcock propose that an evolutionary tug of war between genes from the father’s sperm and the mother’s egg can, in effect, tip brain development in one of two ways. A strong bias toward the father pushes a developing brain along the autistic spectrum, toward a fascination with objects, patterns, mechanical systems, at the expense of social development. A bias toward the mother moves the growing brain along what the researchers call the psychotic spectrum, toward hypersensitivity to mood, their own and others’. This, according to the theory, increases a child’s risk of developing schizophrenia later on, as well as mood problems like bipolar disorder and depression.

In short: autism and schizophrenia represent opposite ends of a spectrum that includes most, if not all, psychiatric and developmental brain disorders. The theory has no use for psychiatry’s many separate categories for disorders, and it would give genetic findings an entirely new dimension.

What’s going on is not so much a “turning on or off” of genes but a “muffling” or “altering” of a gene “with a chemical marker that makes it hard for the cell to read the genetic code.” To illustrate how such an altering of a gene can present itself in seemingly opposite conditions, Dr. Crespi and Dr. Badcock point to Angelman Syndrome and Prader-Willi Syndrome, which both involve genetic disruptions on chromosome 15. Individuals with Angelman Syndrome have a “stiff, jerky gait, absent speech, excessive laughter and seizures.” Those with Prader-Willi Syndrome have “low muscle tone, short stature ….., incomplete sexual development, and a chronic feeling of hunger that, coupled with a metabolism that utilizes drastically fewer calories than normal, can lead to excessive eating and life-threatening obesity.” If the father’s genes dominate in the region of chromosome 15, a child develops Angelman Syndrome; if the mother’s genes dominate in that same region of chromosome 15, a child has Prader-Willi Syndrome: “The former is associated with autism, and the latter with mood problems and psychosis — just as the new theory predicts.”

Dr. Badcock noted similar contrasts in autism and schizophrenia, in terms of eye gaze (while autistic persons fail “to meet another’s gaze,” people with schizophrenia “often believe they are being watched”) and the notion that autistic persons are “mind-blind” and unable to infer others’ intentions and feelings, while (in contrast) “people with schizophrenia see intention and meaning everywhere, in their delusions.”

A number of scientists are quoted in the New York Times article as noting that the theory seems potentially “plausible” while yet “wrong” in terms of many of its details. The theory seems to draw much on theories of autism developed by psychology professor Simon Baron-Cohen, such as his work on mind-blindness and autistic persons lacing empathy, and on the notion that autism is the manifestation of the “extreme male brain,” according to which men are systemizers/engineers, while empathy is associated with the “female” brain. I’ve wondered often about expressions of empathy as displayed by my son; certainly, his tendency to systematize is apparent in his creation of patterns of order for himself. I do rather suspect, at least a few mothers will raise an eyebrow to find themselves even theoretically linked to a “psychotic spectrum,” however much it’s linked with a “hypersensitivity” to mood and feelings.

The male/systemizer and female/empathizer categories don’t fall into place very neatly in my own household. I’m more likely to set a few principles of order around here and Jim is very much, intuitively, attuned to what others are sensing and feeling—-how “sweeping” will this new theory be?

Linking autism to rates of rainfall could be said to be a quite extensive attempt to find an environmental cause of autism, and one that is clearly external and not genetic. Since the study was reported earlier this week, it’s been getting a lot of press. Two genetic studies were also recently noted this week: Ars Technica looks closely at one study on language genes. Another study published in the Archives of Pediatric and Adolescent Medicine looks at parents’ concerns about their own risk and their children’s risks for genetic disease. With the development of genetic testing and, too, of direct-to-consumer genetic tests, parents can find out a lot more about their genetic profile and quite readily.

Is there a tendency to shy away from genetic theories of autism because of parental guilt about giving children “bad genes”?

Researchers from the Seaver and NY Autism Center of Excellence at New York’s Mount Sinai School of Medicine have developed a new method to detect copy number variants associated with autism spectrum disorders and have also found new chromosomal duplications that can be linked to autism.The study is published in the October 16th BMC Medical Genomics.

279 child with ASDs were screened for micro-duplications and -deletions in regions of the genome that have been connected to other cognitive conditions. The researchers detected several previously known duplications associated with autism, but also some that had not previously been recognized. The approach that psychiatry researcher Joseph Buxbaum and his colleagues used is multiplex ligation-dependent probe amplification, or MLPA which, it’s underlined, is an inexpensive and “efficient method to screen or chromosomal abnormalities,” whether these are large or small duplications.

Here’s a summary of the study from Genome Web:

The researchers screened 279 unrelated children with ASD using four different MLPA panels targeted parts of the genome previously linked to cognitive impairment. The subjects, who were around 8 years old, were not pre-selected based on dysmorphism or cognitive defects, Buxbaum said.

After weeding out copy number variants that were found in healthy controls and validating micro-deletions or -duplications using fluorescence in situ hybridization, quantitative PCR, or direct sequencing, the researchers found that about one to two percent of those with ASD also had a chromosomal abnormality associated with cognitive impairment.

For instance, they found subjects with duplications in a chromosome 15 region known to be involved in Prader-Willi/Angelman syndrome, a region of chromosome 22 that’s linked to DiGeorge syndrome, and a region of the X-chromosome that’s associated with X-linked non-specific mental retardation. The team also detected subjects with a partial duplication in the ASMT gene, which is found in the pseudoautosomal region 1 of sex chromosomes and has been previously linked to ASD.

Although the approach is quick and easy, Buxbaum cautioned, MLPA can’t be used to find new, unknown mutations — a situation that may occur in autism. That means it could miss private mutations that could be caught using array CGH with a dense chip.

In contrast, array CGH is “very expensive and time consuming.”

Buxbaum notes that these findings are mostly significant for an etiological understanding of autism and to starting a child on therapy as soon as possible:

………he emphasized, it would be unrealistic and undesirable to think of applying this sort of test in a prenatal setting, particularly because the individual mutations associated with autism are often incredibly rare, often with a vast range of expressivity. In cases where there is a family-member with a known genetic condition, Buxbaum noted, genetic testing for that specific condition can sometimes be desirable.

“Every time you say genetic testing, some people automatically think of pre-natal testing,” Buxbaum said. “This is more about giving an etiological diagnosis to children with autism.”

Multiplex ligation-dependent probe amplification for genetic screening in autism
spectrum disorders: Efficient identification of known microduplications and
identification of a novel microduplication in ASMT can be read as a PDF file.

Currently, there’s no prenatal genetic test for autism. Long ago (as in “around the time I first started writing this blog”) I referred to such testing as “fighting word“: While some would welcome the notion of knowing that a child-to-be would have a disability, others have been quick to point out the possibility of people choosing to abort a fetus if a disability were detected.

In the October 13th Babble, an online web community for a “new generation of parents,” Karen Dempsey writes about Choosing (a) Life: They said our baby would have Down’s; we said we understood. We had no idea. Having conceived her second child after a year of infertility treatments, Dempsey was concerned that the “risks of amniocentesis outweighed the chances it would detect a problem.” During an ultrasound, the radiologist detected other possible signs of Down Syndrome (echogenic intracardiac focus, or EIF; the size of the baby’s nose). Dempsey and her husband knew they were going to have their baby, no matter what. The article depicts Dempsey’s emotional state and thoughts while awaiting her daughter’s birth:

One sleepless night near the end of my pregnancy, I lay in bed with my heart racing, remembering that tiny star from the ultrasound. Were we kidding ourselves, pretending we could just take things as they came? I couldn’t calm myself, though I was desperate to sleep. I tried relaxing by tightening and releasing the muscles of my body one by one, beginning at my toes. I should pray, I thought. I should pray for her. But what did that mean? She was there, fully formed inside of me. I could feel her knees and elbows, her stubborn round head. I didn’t believe in a prayer that would change her genetic makeup; she had Down syndrome, or she didn’t. And so what would I be asking for, a different baby? I’d already chosen to have this one. I finally found peace, and sleep, with the thought, She is who she is. Already, she is who she is, and she is mine.

Liddy does not have Down’s Syndrome, but she has a number of medical conditions: a heart murmur caused by a congenital heart defect, swollen kidneys, an elevated white blood cell count, severe gastroesophogeal reflux disease. Dempsey writes of what testing could have told her and what it could not have:

An amniocentesis would not have predicted Liddy’s complications, or prepared me for the realities of having a sick child. Caring for Liddy challenged my marriage, my family relationships, my friendships and my mental health — my very way of being in the world. John and I were naïve. We would learn, through Liddy, the awe-inspiring breadth of medicine’s understanding, as well as the frustration and grief of its limitations — and of our own.

There’s no question in my mind that we were going to have Charlie when I was expecting, “whatever” he might have. Dempsey’s experience seems to me a potential harbinger of questions that parents may find themselves facing should more prenatal tests be developed, including these tough questions:

Will medicine suggest that any and every variation from absolute normalcy is pathological?

How can we draw lines between disabling diseases such as severe autism and more mild differences such as Asperger’s, which may give society some of its greatest achievers?

Will parents have complete say over the kind of children they want to bear?

And what sorts of messages will doctors and genetic counselors convey when talking about risks, probabilities and choices that involve not life and death but personality and sociability, genius and geekiness?

Tough questions and big questions. Here’s two perspectives, one from a scientist and another from the father of an autistic daughter.

For myself, I would to some extent have appreciated knowing Charlie’s diagnosis as early as possible. Perhaps it’s from the memory of all my wondering, worries, and confusion during Charlie’s babyhood, when subtle things said “things are different,” but nothing stood too much out, and no one wanted to say “maybe he needs to be evaluated by a specialist.” On the other hand, before there might be such a test, it seems all the more imperative to—like parents of children with Down Syndrome—present a hopeful message out there about autism, with an emphasis on how it’s not a dreadful death sentence, and that we know a lot more and can help a child greatly.

When I tally up all the things that have happened to Jim and Charlie and me since Charlie was diagnosed, it’s a rich harvest of experience, with some really tough and awful times (because society and communities did not know what supports and services to provide him with to thrive) and some so good, you can’t imagine life without them.

Following up on the harvest theme, today is “harvest theme day” at the b5media Health and Wellness channel. Wishing you a day of plenty and of sunshine, and of good times with those who walk with you.

So as you may not, or may, have noticed, there is still some wonkiness going up with this blog. The good folks who handle are matters technological, software-related, and the like, have been working hard to migrate b5media’s blogs over to a new server and all should be well, webpages should load and updates occur, very soon. One (”adverse effect?“) of the server migration has been that the sidebar (to your right) has not been updating with recent posts and recent comments. So if a comment is left on a post written a couple weeks or months ago, unless you’ve decided to sit down and read every single post (which I don’t recommend; some posts are more post-worthy than others), some good comments will go missed. I’ve rounded up a few of them below, with a bit of my own responses, and many many thanks for everyone who reads Autism Vox and lets me know what you think.

Anatasia Hulke was found on Monday afternoon, after she’d been missing from her home since Thursday.Regan commented on a bulletin about educational policy from the National Down Syndrome Society and pointed out a Nova video about autism, genes, and a tale of two mice.

A post about late talking written in July continues to draw comments, including this one from John which argues that autism and other disabilities like dyslexia are currently over-diagnosed.

I would counter, they are being diagnosed more because we understand them more and can better identify them, and this notion of better diagnosis needs to be considered in investigating why the rates of autism in Somali children in Minneapolis have increased (here is a commenter, Ali, on this topic).

A commenter, Mindy, asked another commented about seizure medications, Sensory Processing Disorder in a post on sensible accommodations for sensory issues. A couple of friends have been talking on and off about the possibility of using medication for their children. My son’s been on medication since he was 7 and the decision to use it was not lightly made; the medications’ effects are carefully, continually scrutinized. (We’re going to visit Charlie’s pediatric neurologist on Friday to talk about this and some other things.)

The father of a teenage boy asked this question in a post on talking to oneself:

I’ve noticed my 16 yr old boy pace and talk to himself a few times. He is still a bit uncoordinated and has a tendency to walk looking down instead of his head up or stragit ahead. He has above average grades and excels in Japenese but he is a bit sluggish with physical acitivities. I’m a bit concerned becasue his mother (the ex) suffers from schizophrenia and his older brother devleoped a psychois at about 20 yrs of age but had bad grades and drug use may have contributed. Should I be concerned?

Some things I’d ask: Are the pacing and the looking down and the sluggishness long-time behaviors, or relatively new? Are these things affecting him in school or otherwise; does he generally seem happy and all right with things? If he only talking to himself, or also talking to others? Just some thoughts……

Another commenter, Jim Blair, asked me a question in the midst of a comment, quoted here in full; the original post was on prenatal testing (a topic of particular now because of whose youngest son, Trig, has Down Syndrome:

Kristina Chew says:

“And a life without Charlie is a life that neither I nor my husband Jim can imagine, nor would we want to.”

Hi,

Follow me in a hypothetical thought experiment. Imagine that your Charlie had been born a “perfect child” as seen by most people. Suppose he were to grow up to be–depending on your preference, an all star New York Yankee shortstop or Nobel Prize winning scientist. Call him Charlie II.

Would you then make the above quoted claim?

Now suppose that as the result of prenatal genetic testing Charlie I had been aborted and 6 month later Charlie II conceived. Think you would still choose the Charlie I that was never born to the Charlie II that was never conceived?

Of course not. Because we only know the things that ARE and not the things that might have been had we made different decisions.

I thank Jim Blair for taking the time to write out this thought experiment, though I find him to be a bit presumptive about how I would respond to his question. According to him, had I known via prenatal testing that Charlie (”Charlie I,” in the thought experiment) had autism, I would have chosen to abort him, thus making it possible for the conception and eventual birth of a most hypothetical “Charlie II” who would grow up to be an “all star New York Yankee shortstop or Nobel Prize winning scientist” and who, endowed with such an impressive future, would be a child that people would wish to have, and would indeed even consider to be a, if not the, perfect child.

I hope that Jim Blair keeps reading this blog (especially once the software issues gets resolved), as he will then find out why I know that Charlie is perfect and why there was no never any doubt in anyone’s mind that he, once conceived, would be born, and that whatever prior information Jim and I might have from prenatal genetic testing or other testing, we have always chosen to have him.

Always have, always will.

BTBR mice are an inbred mouse strain that provide a “mouse model of autism.” BTBR mice are transgenic (their DNA contains an extra human gene thought to be involved in autism) and display “social abnormalities and repetitive behaviors” that correspond to the first and second diagnostic criteria for autism spectrum disorders. A recent study in PLOS One by Maria Luisa Scatton et al. investigates ultrasonic vocalizations in BTBR mice, in order to look at the second diagnostic criterion for ASDs, communication deficits. Scientists separately baby mice of different strains from their mothers and hypothesized that ultrasonic vocalizations might be a measure of social communication in the mice. As The New Scientist notes:

The pups, which had not yet opened their eyes, made noises aimed to bring mom back. These ultrasonic sounds � too low for the human ear to detect � come in 10 different types, from clicking to pure tones.

Most mice in the study used all 10 categories. But the vocabulary of one strain, called BTBR, was limited to four calls, focusing on “harmonics” that contain multiple, simultaneous sounds � like guitar strings plucked together. BTBR mice also called louder and for longer periods of time. “This is similar to what others have found in autistic infants,” says Scattoni.

Via The New Scientist is a clip of the sounds a BTBR mouse makes. A press release also notes this:

The reduced vocal repertoire in BTBR mice may be analogous to atypical vocalizations in some infants and young children later diagnosed with autism. Instead of cooing and babbling, some young children may hum or grunt for extended periods, fail to add inflections into speech patterns, repeat “pop up” words out of context, squeal stereotypically, and laugh inappropriately. Others may be very irritable, cry for long periods of time, and be difficult to console. More crying in these babies may be similar to the higher number of separation calls in BTBR pups.

And, as the authors of the study note, “Mouse pup calls incorporate some properties that suggest they could serve some of the same functions as the crying of human babies, especially their ability to elicit parental retrieval behaviors.”

Never having paid too much attention to repetitive patterns of squeaking in any mouse (like the large gray one that once walked into a glue trap in our old kitchen), I do note certain repeated sounds and frequences in the audio clip of a BTBR mouse vocalizing. But then, I am listening for certain sounds and patterns of sounds.

The “atypical vocalizations” in young children later diagnosed with autism that are considered similar to  those of the BTBR mice—humming or grunting “for extended periods, failing to ” inflections into speech patterns,” repetition of “‘pop up’ words out of context”—were features of Charlie’s communication when he was very young, and still can be heard today.It’s noted that researchers hope to use these findings in “identifying genetic and environmental causes of autism, and for evaluating proposed treatments.” But I’m wondering if the study also simply sheds some light about the non-verbal communication of autistic children. We strive constantly to encourage and improve Charlie’s talking, but we’ve also learned to tune in to his non-verbal communication, to his vocalizations. These are often musical, having a melody, rhythm, pitch, tone, phrasing. Charlie’s verbal communication is limited, but he is (and always has been) communicating, and in ways that we need to learn to listen to.

One mouse’s (boy’s) noise is saying something.

Could it be something in the water? The answer might seem “yes” if all you read is the headline of an article in today’s Scotsman:

Study reveals water’s role in rare autism

The water in question is not the wet stuff in oceans, lakes or rivers or in pools (where we’re shortly headed to—I told you Charlie liked swimming and I meant it!). It’s water at the molecular level, and is linked to Rett Sydrome, which has been linked to a mutation in the MECP2 gene:

Researchers discovered that Rett’s syndrome is caused by the Mecp2 protein interacting with water trapped around the DNA rather than reacting directly with the DNA itself.

Professor Adrian Bird [of University of Edinburgh], who took part in the study, said: “We thought this process involved oily components sticking together, but we didn’t expect oily contact to depend on water – because, of course, oil and water don’t mix.

“The discovery has enabled us to understand the reasons why the mutated proteins fail to function properly in Rett patients.”

Professor Bird’s lab is creating a mouse model of Rett Syndrome by targeted mutation of MECP2.

A new study suggests that microRNAs (miRNAs)—a type of RNA (ribonucleic action), which is involved in protein synthesis—-may play a role in the development of autism. miRNAs are “abundant in the brain” and have a role in neurological diseases such as Tourette’s sydrome and Fragile X syndrome. Noting that autism is a “genetically complex disease,” researchers considered whether dysregulation of miRNA expression might play a role in autism. Specifically, the new study found that miRNAs can bind to longer RNA sequences and prevent them from making protein; according to Professor Kenneth S. Kosik, as quoted in a press release:

“It was of interest to find that various members of the microRNA family are frequently dysregulated in autism……This result points to a single control layer in the cell that can change in quite different ways with autism as the end result.”

The researchers found that genes which are “known genetic causes of autism”— Neurexin and SHANK3—were “among the predicted targets of dysregulated miRNAs.” Here’s the full abstract:

microRNAs (miRNAs) are ~21 nt transcripts capable of regulating the expression of many mRNAs and are abundant in the brain. miRNAs have a role in several complex diseases including cancer as well as some neurological diseases such as Tourette’s syndrome and Fragile x syndrome. As a genetically complex disease, dysregulation of miRNA expression might be a feature of autism spectrum disorders (ASDs). Using multiplex quantitative polymerase chain reaction (PCR), we compared the expression of 466 human miRNAs from postmortem cerebellar cortex tissue of individuals with ASD (n = 13) and a control set of non-autistic cerebellar samples (n = 13). While most miRNAs levels showed little variation across all samples suggesting that autism does not induce global dysfunction of miRNA expression, some miRNAs among the autistic samples were expressed at significantly different levels compared to the mean control value. Twenty-eight miRNAs were expressed at significantly different levels compared to the non-autism control set in at least one of the autism samples. To validate the finding, we reversed the analysis and compared each non-autism control to a single mean value for each miRNA across all autism cases. In this analysis, the number of dysregulated miRNAs fell from 28 to 9 miRNAs. Among the predicted targets of dysregulated miRNAs are genes that are known genetic causes of autism such Neurexin and SHANK3. This study finds that altered miRNA expression levels are observed in postmortem cerebellar cortex from autism patients, a finding which suggests that dysregulation of miRNAs may contribute to autism spectrum phenotype.

The study, Heterogeneous dysregulation of microRNAs across the autism spectrum, was published June 19 in Neurogenetics by researchers from the Neuroscience Research Institute, and Department of Molecular Cellular and Developmental Biology, University of California Santa Barbara.

Researchers at Adelaide’s Women’s & Children’s Hospital and the University of Adelaide, Australia, have found that a mutant gene causes epilepsy and intellectual disabilities specific to women. As noted in Science Daily, the study links a “large family of genes known as protocadherins with a condition known as ‘epilepsy and mental retardation limited to females’ (EFMR).” EFMR is described as “relatively uncommon” and also hereditary,

…….with successive generations of women affected. In just one of seven families studied across the world, 23 women were affected by the disorder across five generations. This discovery will now enable such families to benefit from genetic counselling, including screening for the genetic mutation at pregnancy.

“This is the first time this type of gene has been found to be involved in epilepsy,” Dr [Leanne] Dibbens [one of the leaders of the study] says.

“One of the most important discoveries we’ve made is that women in families affected by EFMR carry both a ‘good’ gene and a ‘bad’ (mutated) gene, while the men carry only the bad gene. For some reason, the men remain unaffected by the condition,” Dr Dibbens says.

“We suspect this may have something to do with the male Y chromosome, but more research will be needed to find out exactly how or why.”

Of course, epilepsy and intellectual disabilities are not found in all autistic women, but these are among the co-morbid conditions that can occur with autism. Dibbens will be continuing her research by studying “larger groups of patients with epilepsy, intellectual disability, and a number of the females affected in these families have autistic features and obsessive features,” as she notes in a May 12th interview with The World Today.

The study is published in Nature Genetics.